Post-traumatic stress disorder and childhood emotional abuse are markers of subthreshold bipolarity and worse treatment outcome in major depressive disorder

Post-traumatic stress disorder (PTSD) and childhood maltreatment (CMT: parental neglect; emotional, physical and sexual abuse) have been linked to bipolar disorder but they are also common in major depressive disorder (MDD). Our objective was to investigate their association with the bipolar spectrum and antidepressant treatment outcome in 482 outpatients with DSM-IV MDD treated in the Combining Medications to Enhance Depression Outcomes trial for 28 weeks Bipolar spectrum score included age of onset <21 years, subthreshold hypomania (a period of elated or irritable mood with at least two concurrent hypomanic symptoms, which did not fulfill DSM criteria for hypomanic/manic episode) and depressive mixed state (DMX). PTSD subjects (n = 107; 22%) had more severe depression (P < 0.0001), work and social impairment (P = 0.0031), comorbid anxiety disorders (P < 0.0001) and increased suicidality (P = 0.0003). Bipolar spectrum score was higher with PTSD comorbidity (P = 0.0063) and childhood emotional abuse (P = 0.0001). PTSD comorbidity was associated with residual suicidality (P = 0.0218) after 6 weeks of antidepressant use whereas childhood emotional abuse [odds ratio (OR), 1.01–2.22], subthreshold hypomania (OR, 1.04–4.09) and DMX (OR, 1.00–4.19) were predictors of mood switch. These results corroborate the role of PTSD and childhood emotional abuse as markers of bipolar spectrum and prognostic factors during antidepressant treatment.


Introduction
On the basis of current diagnostic criteria, bipolar disorders are only identifiable by ascertaining manic or hypomanic episodes. This approach is not devoid of weaknesses (Nusslock and Frank, 2011). A first concern is that in bipolar patients the onset of mood activation is often preceded by a large number of depressive episodes, thus there is a lengthy time period from the point of illness onset to correct diagnosis. Second, milder, albeit clinically significant, bipolar spectrum syndromes would be included, by default, in major depressive disorder (MDD), with detrimental effects on illness course (e.g. manic switch and rapid cycling) related to inappropriate treatment. In the last few decades, a great research effort has allowed identifying reliable markers of bipolarity such as mixed depression [i.e. a major depressive episode (MDE) with few concurrent hypomanic symptoms] Benazzi, 2005;Perugi et al., 2015) and subthreshold hypomanic episodes occurring outside depressive phases (Angst et al., 2003;Zimmermann et al., 2009;Serretti et al., 2021). Notwithstanding this progress, whenever information on prior manic or hypomanic episodes is not available, the correct identification of bipolar depression remains a challenge. In this context, post-traumatic stress disorder (PTSD) might deserve attention as a marker of bipolar spectrum. PTSD comorbidity involves up to one-third of patients with major depression (Green et al., 2006;Campbell et al., 2007) but several lines of evidence support its connection with bipolar disorder. For instance, it is known that individuals who have been exposed to traumatic experiences or complicated grief and exhibit PTSD manifestations are at increased risk of developing hypomanic symptoms (Dell'Osso et al., 2012). PTSD is actually one of the most frequent diagnoses in patients with bipolar disorder (Otto et al., 2004;Goldberg and Garno, 2005;Neria et al., 2008;Assion et al., 2009) and vice-versa (Hernandez et al., 2013;McLay et al., 2014). Moreover, the likelihood of PTSD in bipolar subjects is 4-5 times higher relative to patients with MDD (Dilsaver et al., 2007(Dilsaver et al., , 2008. Childhood maltreatment (CMT)which includes parental neglect, emotional abuse, physical abuse and sexual abuseis even more related to bipolar illness. In a meta-analysis individuals with bipolar disorder were 2.6 times more likely to report CMT compared to non-clinical controls (Palmier-Claus et al., 2016). Additionally, among bipolar subjects, those This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. who had been exposed to CMT were more likely to experience their first episode earlier (Larsson et al., 2013) as well as to develop rapid cycling and suicidal behavior Etain et al., 2013;Aas et al., 2014). CMT has also been linked to suicidality. In the most comprehensive review, which analyzed over 260 000 individuals from 68 studies, CMT was associated with twofold to three-fold increased risks for suicide ideation and attempts (Angelakis et al., 2019).
The aim of this study was to investigate the diagnostic and prognostic roles of PTSD and CMT in MDD, to disentangle their association with bipolar spectrum, the likelihood of mood activation and the persistence of suicidal tendency during antidepressant use.

Sample
This study was a secondary analysis of the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, which was carried out at six primary care sites and nine psychiatric care centers across the USA (Rush et al., 2011). Eligible subjects were of age 18-75 years, with DSM IV-based MDD and HDRS 17 scores ≥16. Exclusion criteria were psychotic depression or bipolar (DSM IV) illness and admission to psychiatric inpatient facilities. The CO-MED trial enrolled 665 subjects from March 2008 to September 2009. Our analysis involved 482 participants recruited until February 2009.

Ethical issue and informed consent
The CO-MED trial was conducted according to the Principles of Helsinki Declaration and its protocol was reviewed and approved by ethical committees at local recruitment sites (Rush et al., 2011). All subjects selected by clinicians were included in the screening phase after obtaining their written informed consent. This research group certifies that data collected for the CO-MED trial were exclusively used for scientific investigation. Before obtaining access to data, the objectives of our investigation were clearly described in the request form (Serretti et al., 2021).

Treatments
CO-MED was designed as a single-blind (participant only), placebo-controlled trial in which eligible subjects were randomly assigned to one of the following treatment arms: (1) escitalopram plus placebo; (2) bupropion SR plus escitalopram and (3) venlafaxine XR plus mirtazapine. The trial included a short-term (12 weeks) treatment followed by a continuation phase (weeks 12-28) (Rush et al., 2011).

Assessment
Sociodemographic characteristics were collected by means of a specific form including age, gender, ethnic group, education and monthly income (Rush et al., 2011). The Mini-International Neuropsychiatric Interview (M.I.N.I) (Sheehan et al., 1998) was used to validate the diagnosis of MDD and exclude psychotic and bipolar illness, to assess some clinical features such as chronic or recurrent depression, the number of past depressive episodes and age at onset of the first episode and to ascertain the lifetime occurrence of subthreshold hypomanic episodes (see below). Depressive episode was thoroughly assessed by administering the 30-item Inventory of Depressive Symptomatology-Clinician Rating (IDS-C 30 ) (Corruble et al., 1999) and the 16-item Quick Inventory of Depressive Symptomatology (QIDS-C 16 ) (Rush et al., 2003), the Concise Associated Symptoms Tracking (CAST) (Trivedi et al., 2011a) and Concise Health Risk Tracking (CHRT) (Trivedi et al., 2011b) scales, which respectively, assessed irritability and suicide propensity and ideation, the Altman Self-Rating Mania Scale (ASRM) (Altman, 1998) to ascertain intra-MDE hypomanic symptoms and the Work and Social Adjustment Scale (WSAS) (Mundt et al., 2002) to ascertain functional impairment. The individual assessment was completed by the Psychiatric Diagnostic Screening Questionnaire (PDSQ) (Zimmerman and Mattia, 1999), which investigated comorbid PTSD (post-traumatic scale ≥8) and anxiety disorders, and a questionnaire that was specifically developed to explore CMT subtypes (Medeiros et al., 2021).

Antidepressant treatment outcome
In prior CO-MED analysis, Medeiros and colleagues (2021) investigated the impact of CMT on antidepressant-treatment outcomes. Here, instead, we focused on PTSD comorbidity and analyzed its association with response (>50% decrease in QIDS score from baseline) and remission (QIDS≤5) after six weeks of antidepressant use. In addition, we analyzed the association of PTSD and CMT with residual levels of suicide propensity and ideation (CHRT) as well as with mood activation (ASRM score ≥6) (Altman, 1998) occurring after ≥14 days of antidepressant use. set at alpha = 0.025. Multivariate analysis was conducted by means of multiple regression and multiple logistic regression (MLR) analysis including variables with P ≤ 0.10 at the univariate level. Statistical software was OpenStat version 8 December 2014 (https://openstat. info/OpenStatMain.htm).

Post-traumatic stress disorder comorbidity and bipolar features
The mean age at depression onset was 23.35 ± 13.50 years but in 262 subjects (54%) the first episode occurred before 21 years of age. 68 subjects (14%) met the criteria for DMX and 48 (10%) for subthreshold hypomania. Comparisons of bipolar features by PTSD classifier are displayed in Table 2. The PTSD group was found to differ from individuals without PTSD in terms of younger age at depression onset (t = 2.48; P = 0.0136), greater lifetime presence of subthreshold hypomania (Chisquare = 5.39; P = 0.020) and higher bipolar spectrum score (t = 2.77; P = 0.0063). Conversely, the distribution of DMX was not statistically different between the two groups. Among bipolar spectrum symptoms, irritability (CAST: t = 3.86; P = 0.0002), increased talkativeness (t = 2.86; P = 0.005) and reduced need for sleep (t = 2.67; P = 0.0084) showed the strongest association with PTSD. By performing MLR analysis, bipolar spectrum score emerged as an independent predictor of PTSD (OR, 1.05-1.54) along with irritability (OR, 1.14-3.76), difficulty in falling asleep (OR, 1.03-1.54) and middle nocturnal insomnia (OR, 1.02-1.61) ( Table 2). The association between bipolar spectrum score and PTSD was no more significant (OR, 0.99-1.48) when CMT subtypes were added to other variables; thus, the new PTSD predictors became irritability (OR, 1.12-3.81), difficulty in falling asleep (OR, 1.02-1.55), middle nocturnal insomnia (OR, 1.01-1.61) and childhood physical abuse (OR, 1.05-3.63) ( Table 2).

Discussion
In our sample, about one in five patients had PTSD comorbidity. This figure was distant from 50 to 70% reported in Veteran outpatients (Zisook et al., 2016;Mohamed et al., 2020) and socioeconomically disadvantaged groups (Grote et al., 2016), but substantially similar to 33-36% displayed in other clinical samples (Green et al., 2006;Campbell et al., 2007). Instead, the prevalence of PTSD was significantly lower in the Sequenced  Treatment Alternatives to Relieve Depression study (STAR*D), which only identified 122 cases from 2280 participants (5%) (Steiner et al., 2017). Such a difference was not related to PTSD assessment, which was conducted via PDSQ administration as well, but it could reflect the larger proportion of patients (54%) in our sample who were victims of maltreatment during childhood and, consequently, exposed to traumatization.

Diagnostic role of post-traumatic stress disorder and childhood emotional abuse as markers of subthreshold bipolarity
A clear-cut result of our study was to associate PTSD and childhood emotional abuse with a variety of bipolar validators assessed lifetime (Angst et al., 2003;Benazzi, 2009;Zimmermann et al., 2009;Mazzarini et al., 2018) and during a single MDE (Benazzi, 2001(Benazzi, , 2005(Benazzi, , 2008Akiskal et al., 2005;Perugi et al., 2015). These findings are largely consistent with epidemiological data that suggest high levels of diagnostic comorbidity between PTSD and bipolar disorder (Otto et al., 2004;Graves et al., 2007;Neria et al., 2008;Hernandez et al., 2013;McLay et al., 2014). Moreover, prior to ours, other studies have displayed a correlation between childhood adversity and bipolar features in major depressed patients (Park, 2017). It is plausible that childhood traumas and maltreatment are not simply more widespread among subjects with bipolar disorders (Janiri et al., 2015;Palmier-Claus et al., 2016) but, rather, risk factors for bipolar illness (Quide et al., 2020). The comorbidity between PTSD and bipolar disorder could be explained by the overlap of some symptoms between these conditions. In particular sleep disturbance, difficulty concentrating, increased risk-taking behavior and irritability are often reported in patients with PTSD and bipolar disorders (Cogan et al., 2021) and they also represent the typical profile of mixed depression (Perugi et al., 2015;Brancati et al., 2019). Therefore a valuable result of this study was to demonstrate that control for irritability, insomnia and poor concentration did not modify the association between bipolar risk score and PTSD. This would suggest that the co-occurrence of PTSD and bipolar spectrum disorder might be true comorbidity rather than a mere artifact, although there is a need for further studies to corroborate this hypothesis. However, if experiences of CMT were added to irritability and insomnia, the association between bipolar risk score and PTSD was no more significant. Overall these results seem to indicate that the association between bipolar spectrum and PTSD could be at least in part mediated by CMT. Nevertheless, further studies are necessary to ascertain the effectiveness of assessing PTSD symptoms and childhood maltreatment in patients with DSM unipolar depression in order to improve the identification of bipolar spectrum disorders.

Prognostic impact of post-traumatic stress disorder and childhood emotional abuse
We found that the presence of PTSD was associated with more severe depressive symptoms, notably higher negative self-outlook, anxiety and insomnia, work and social impairment and increased suicidal tendency. This  ASRM, Altman Self-Rating Mania Scale (Altman, 1998); CI, confidence interval; OR, odds ratio; PTSD, post-traumatic stress disorder.
picture was consistent with prior studies suggesting that subjects with comorbid major depression and PTSD might have more psychopathological manifestations as well as a higher suicide risk than those with either condition alone (Morina et al., 2013). Moreover, our findings mirrored those emerging from the STAR*D study, which displayed the impact of PTSD comorbidity on depression severity and functional impairment as well (Steiner et al., 2017). As baseline clinical severity was found to negatively affect antidepressant treatment outcomes (Friedman et al., 2012), we expected that PTSD comorbidity was associated with a less favorable antidepressant response. Such a correlation had been documented in STAR*D sample (Steiner et al., 2017). Conversely, we failed to demonstrate any association between PTSD and antidepressant-related outcomes. This result was in line with a recent study, based on CO-MED data like the present one, in which exposure to CMT had no impact on antidepressant response (Medeiros et al., 2021). Nevertheless, PTSD might exert a negative prognostic influence on major depression. Indeed, in our sample, PTSD group was characterized by higher levels of the residual propensity for suicidal behavior after acute antidepressant treatment and this association was confirmed even accounting for the higher degree of suicidality reported at baseline.
Another outcome variable analyzed in the current study was the new onset of mood activation symptoms during antidepressant use. The occurrence of hypomanic symptoms within a depressive episode of unipolar disorder was already investigated using CO-MED sample (Jha et al., 2018). In that study, patients who endorsed hypomanic symptomatology were characterized by lower remission rates with escitalopram monotherapy and venlafaxine plus mirtazapine combination. Instead, our results corroborated the role of intra-MDE hypomanic symptoms and sub-threshold hypomanic episodes in predicting mood switch during antidepressant therapy. Interestingly, a similar correlation with mood activation was shown by childhood emotional abuse. These findings are intriguing and provide new evidence about predictors of mood activation in apparently unipolar depression (DelBello et al., 2003;Celik et al., 2016).

Stregth and limitations
This study analyzed in detail depressive symptomatology and bipolar features using both cross-sectional and longitudinal approaches. Axis I comorbidities were also carefully assessed. Hence, it was possible to disentangle the effect of several potential confounding variables while investigating the association between PTSD comorbidity and bipolar spectrum. The onset of mood activation during antidepressant treatment is a concern for clinicians and our study provided some cues to predict this risk. On the other hand, the main limitations are related to the post hoc nature of our analysis and to the retrospective approach used to investigate a large number of variables (e.g. onset of the first depressive episode; lifetime occurrence of subthreshold hypomania; CMT, etc). Moreover, common symptoms of mixed depression such as thought racing, distractibility or reckless activity could not be assessed using the ASMR scale, thus the prevalence of DMX could have been underestimated as well as some reliable bipolar validators (e.g. family history) were not available. Finally, there is evidence that the effects of childhood emotional abuse on suicidality are at least in part mediated by emotional abuse and depressive symptoms experienced in adulthood (Lee, 2015). Therefore, a caveat of this study was that it could analyze emotional abuse during childhood but not re-victimization in adult age.

Conclusion
Maltreatment experiences occurring in childhood and PTSD symptoms in adult age are commonly reported by subjects with MDD. Their presence is associated with severe forms of depression and, as suggested by current data, they might be putative markers of bipolar spectrum. Therefore, PTSD symptoms and CMT should be carefully assessed in all patients who endorse an MDE before choosing pharmacological treatment, in order to minimize risk for a mood activation switch.